Hindawi
Contrast Media & Molecular Imaging
Volume 2018, Article ID 1292746, 9 pages
https://doi.org/10.1155/2018/1292746

Clinical Study
Differential Diagnosis between Low-Grade and High-Grade
Astrocytoma Using System A Amino Acid Transport PET
Imaging with C-11-MeAIB: A Comparison Study with
C-11-Methionine PET Imaging
Ryuichi Nishii ,1,2,3 Tatsuya Higashi ,1,3 Shinya Kagawa,3 Maya Arimoto,4
Yoshihiko Kishibe,3 Masaaki Takahashi,3 Shigeki Yamada,5 Masaaki Saiki,6
Yoshiki Arakawa,7 Hiroshi Yamauchi,3 Chio Okuyama,3 Masato Hojo,8Toshihiro Munemitsu,8 Masahiro Sawada,8 Masato Kobayashi,9 Keiichi Kawai,10
Shigeki Nagamachi,2,11 Toshinori Hirai,2 and Susumu Miyamoto7
1

Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences (NIRS), QST, 4-9-1 Anagawa,Inage-ku, Chiba 263-8555, Japan2
Department of Radiology, Faculty of Medicine, University of Miyazaki, 5200 Kihara Kiyotake-cho, Miyazaki 889-1692, Japan
3
Division of PET Imaging, Shiga Medical Center Research Institute, 5-4-30 Moriyama, Moriyama, Shiga 524-8524, Japan
4
Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University,
54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
5
Department of Neurosurgery, Rakuwakai Otowa Hospital, 2 Otowachinjicho, Yamashina-ku, Kyoto 607-8062, Japan
6
Department of Radiology, Japanese Red Cross Otsu Hospital, 1-1-35 Nagara, Otsu, Shiga 520-8511, Japan
7
Department of Neurosurgery, Graduate School of Medicine, Kyoto University, 54 ShogoinKawahara-cho, Sakyo-ku,
Kyoto 606-8507, Japan
8
Department of Neurosurgery, Shiga Medical Center, 5-4-30 Moriyama, Moriyama, Shiga 524-8524, Japan
9
Wellness Promotion Science Center, Institute of Medical, Kanazawa University, 5-10-80 Kodatsuno, Kanazawa,
Ishikawa 920-0942, Japan
10
Graduate School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University,
5-10-80 Kodatsuno, Kanazawa, Ishikawa 920-0942, Japan
11
Department of Radiology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Correspondence should be addressed to Tatsuya Higashi; higashi.tatsuya@qst.go.jp
Received 29 December 2017; Accepted 6 May 2018; Published 20 June 2018
Academic Editor: Guoqiang Shao
Copyright © 2018 Ryuichi Nishii et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introductions. [N-methyl-C-11]α-Methylaminoisobutyric acid (MeAIB) is an artificial amino acid radiotracer used for PET study,
which is metabolically stable in vivo. In addition, MeAIB is transported by system A neutral amino acid transport, which isobserved ubiquitously in all types of mammalian cells. It has already been shown that MeAIB-PET is useful for malignant
lymphoma, head and neck cancers, and lung tumors. However, there have been no reports evaluating the usefulness of MeAIBPET in the diagnosis of brain tumors. The purpose of this study is to investigate the efficacy of system A amino acid transport PET
imaging, MeAIB-PET, in clinical brain tumor diagnosis compared to [S-methyl-C-11]-L-methionine (MET)-PET. Methods.
Thirty-one consecutive patients (male: 16, female: 15), who were suspected of having brain tumors, received both MeAIB-PET and
MET-PET within a 2-week interval. All patients were classified into two groups: Group A as a benign group, which included
patients who were diagnosed as low-grade astrocytoma, grade II or less, or other low-grade astrocytoma (n  12) and Group B asa malignant group, which included patients who were diagnosed as anaplastic astrocytoma, glioblastoma multiforme (GBM), orrecurrent GBM despite prior surgery or chemoradiotherapy (n  19). PET imaging was performed 20 min after the IV injection of
MeAIB and MET, respectively. Semiquantitative analyses of MeAIB and MET uptake using SUVmax and tumor-to-contralateral

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Contrast Media & Molecular Imaging
normal brain tissue (T/N) ratio were evaluated to compare these PET images. ROC analyses for the diagnostic accuracy of MeAIBPET and MET-PET were also calculated. Results. In MeAIB-PET imaging, the SUVmax was 1.20 ± 1.29 for the benign group and2.94 ± 1.22 for the malignant group (p < 0.005), and the T/N ratio was 3.77 ± 2.39 for the benign group and 16.83 ± 2.39 for themalignant group (p < 0.001). In MET-PET, the SUVmax was 3.01 ± 0.94 for the benign group and 4.72 ± 1.61 for the malignant
group (p < 0.005), and the T/N ratio was 2.64 ± 1.40 for the benign group and 3.21 ± 1.14 for the malignant group (n.s.). For the
analysis using the T/N ratio, there was a signiﬁcant diﬀerence between the benign and malignant groups with MeAIB-PET withp < 0.001. The result of ROC analysis using the T/N ratio indicated a better diagnosis accuracy for MeAIB-PET for brain tumors
than MET-PET (p < 0.01). Conclusions. MeAIB, a system A amino acid transport-speciﬁc radiolabeled agents, could provide
better assessments for detecting malignant type brain tumors. In a diﬀerential diagnosis between low-grade and high-grade
astrocytoma, MeAIB-PET is a useful diagnostic imaging tool, especially in evaluations using the T/N ratio. Clinical trial registration. This trial was registered with UMIN000032498.

1. Introduction

2. Materials and Methods

Positron emission tomography (PET) imaging with aminoacid analogs has been focused greatly on clinical applications, as it targets increased amino acid transport by tumors[1, 2]. Especially for detecting brain tumors, PETstudies withamino acid analogs have been developed [3, 4] to overcome
the drawbacks of F-18 FDG (FDG) PET, such as physiological uptake by the brain [5, 6].
As methionine, an essential sulfur amino acid, is necessary for the growth and development of cells, radiolabelled[S-methyl-C-11]-L-methionine (MET), mainly transported
by system L amino acid transporters [7, 8], has been clinically used as a tumor-seeking agent for PET imaging forseveral decades [9]. MET-PET images can visualize not only
the population and activity of amino acid transport but also
metabolic events inside the body, such as active cell
membrane transport, cellular protein synthesis, polyaminesynthesis, and trans-methylation reactions [10, 11]. However, MET-PET is known to have several drawbacks when
diagnosing tumors. MET is unstable in vivo due to theaminotransfer reaction [10] and is excreted into the bile andintestines. In addition, MET-PET shows faint physiologicaluptake in the brain, strong physiological uptake in the liverand bone marrow, and uptake in certain types of inﬂammatory changes [12, 13].
[N-methyl-C-11]α-Methylaminoisobutyric acid (MeAIB)
is an artiﬁcial amino acid radiotracer used for PET study,
which is metabolically stable in vivo [14]. Although MET istransported mainly by system L neutral amino acid transport,
MeAIB is transported by system A neutral amino acidtransport, which is observed ubiquitously in all types ofmammalian cells [11, 15]. It has already been shown that
MeAIB is useful for amino acid uptake measurements inskeletal muscle and for the diagnosis of malignant lymphoma and head and neck cancers [14, 16, 17]. We havealso been investigating system A amino acid PET molecularimaging with MeAIB to detect tumors and have reported its
usefulness in the diﬀerential diagnosis of pulmonary andmediastinal mass lesions [18] and prostate cancer [19] inclinical practice.
However, there have been no reports evaluating theusefulness of MeAIB-PET in the diagnosis of brain tumors.
The purpose of this study is to investigate the eﬃcacy ofsystem A amino acid transport PET imaging, MeAIB-PET,in clinical brain tumor diagnosis compared to MET-PET.

2.1. Patient Characteristics. From March 2009 to December
2011, 31 consecutive patients (male: 16, female: 15), whowere suspected of having brain tumors, received both
MeAIB-PET and MET-PET within a 2-week interval. Patients’ ages ranged from 5 to 71 years with a mean age of
44.2 ± 18.5, as shown in Table 1. Inclusion criteria for the
study were as follows: (1) patients were suspected of having
an intraaxial brain tumor (newly detected or recurrent lesions 6 months or more after successful treatment) by CT
and MRI (both were performed as routine clinical studies),(2) each patient gave written informed consent and received
MeAIB-PET and MET-PET, and (3) results were conﬁrmed
pathologically, or by clinical follow-up more than 6 months
after the PET studies. Exclusion criteria were as follows: (1)patients with extra-axial tumors such as tumors of themeninges, pituitary tumors, pineal parenchymal tumors, or
cranial nerve schwannomas, (2) patients with metastatic
brain tumors or lymphoma, and (3) patients who refused toreceive MeAIB-PET or MET-PET. Of the 52 patients who
received MeAIB-PET with suspected brain tumors fromMarch 2009 to December 2011, 31 patients were included in
the present study, while the others were excluded because of
the exclusion criteria. According to ﬁnal diagnosis after
surgery or biopsy, all patients who met the criteria wereclassiﬁed into the following two groups: Group A (benign),
which included patients who were diagnosed as low-grade
astrocytoma, grade II including a case of recurrent grade II
glioma or less, or other low-grade astrocytomas (n � 12;
ranging from 5 to 46 years, mean age 32.2 ± 10.0 years; sevenmales and ﬁve females); Group B (malignant), which included patients who were diagnosed as anaplastic astrocytoma, glioblastoma multiforme (GBM), or recurrent GBM
despite prior surgery or chemoradiotherapy (n � 19; ranging
from 14 to 71 years, mean age 56.7 ± 16.8 years; nine males
and ten females).
This prospective clinical study was approved by our
institutional review boards, the Human Study Committee(approval number: #36-04, March 25, 2009) and by theCommittee for the Clinical Use of Short-Half Life Radioactive Materials (approval number: #2008-01, November 28, 2008). All enrolled patients or their parents if thepatient was under 20 years old received explanations, andthen they provided written informed consent regarding thisstudy.

Contrast Media & Molecular Imaging
Table 1: Patient characteristics.
Total (n � 31)
Age (years)
Mean ± SD
44.2 ± 18.5
Median
44
Range
5–71
Male : female
16 : 15
Group A (benign) (n � 12)
Age (years)
Mean ± SD
32.2 ± 10.0
Median
33.5
Range
5–46
Male : female
7:5
Diagnosis
Astrocytoma grade II or less/low-grade glioma
11
Brain stem glioma
1Group B (malignant) (n � 19)
Age (years)
Mean ± SD
56.7 ± 16.8
Median
60
Range
14–71
Male : female
9 : 10Diagnosis
Glioblastoma multiforme
7
Glioblastoma multiforme, recurrence
10Anaplastic astrocytoma, grade 322.2. Radiotracers. Production of MeAIB followed a previously
described procedure [18]. The radiosynthesis method wasbased on that proposed by Nagren et al. [20]. Chemicals andsolvents were of analytical grade and purchased commercially.
[11C]MeOTf was bubbled into the reactor of an automatedremotely controlled synthesizer module C-11-BII (SHI, Tokyo,
Japan) ﬁlled with 1 mg of methyl α-aminoisobutyrate hydrochloride (6.5 mmol) dissolved in 0.4 ml of methanol/acetone(1/1, v/v) and 3.2 μl of 2,2,6,6,N-pentamethyl-piperidine (PMP)at −20°C. Then, the reactor was heated to 80°C for 1 min. Aftercooling to 25°C, 400 μl of 2 M NaOH was then loaded into thereactor. After heating the mixture for 3 min at 60°C, the hydrolyzed product was diluted with 0.5 ml of HPLC eluent andsubsequently transferred to a preparative radio HPLC system
consisting of a preparative HPLC pump (PU-980, JASCO), an
automated ﬂow-detector-controlled injection system with a 2 ml
injection loop, a semipreparative HPLC column (hydrophilic interaction chromatography: HILIC column, Nacalai
Tesque, 250 × 10 mm2, 5 μm; mobile phase: MeCN/10 mM
CH3COONH4, 4/1, v/v; ﬂow: 8 ml/min), a UV detector(254 nm), and an NaI(Tl) radioactivity detector. The productcontaining fraction was then diluted with 10 ml of isotonic saline.
The radiochemical purity of the MeAIB was more than 99%.
MET was synthesized based on the method described ina previous report [21], by the reaction of C-11 methyltriﬂatewith an aqueous solution of L-homocysteine thiolactone ina Sep-Pak tC18 cartridge, followed by puriﬁcation with ionexchange cartridges. The radiochemical purity of MET was
also more than 99%.
2.3. PET Study. All patients were examined with a wholebody PET scanner, GE Advance (GE Healthcare, Waukesha,
WI, USA), or with a whole-body PET/CT scanner, Siemens

3
Table 2: SUVmax and T/N ratios of MeAIB- and MET-PET study
in patients with brain tumors.
Group A (benign group)
MeAIB
T/N
SUVmaxratio
1
Low-grade glioma
0.58
3.22
Astrocytoma grade
2
2.83
8.09
II
3
Low-grade glioma
0.24
1.64
4
Glioma grade II
0.15
1.25
5
Low-grade glioma
0.62
1.11
6
Low-grade glioma
0.85
2.07
7
Brain stem glioma
3.40
4.86
Glioma grade II,
3.49
6.13
8
rec.
9
Low-grade glioma
0.32
4.00
10
Low-grade glioma
0.4
6.67
11
Low-grade glioma
1.34
4.96
12
Low-grade glioma
0.12
1.20
Ave.
1.20
3.77
Group B (malignant group)
13
GBM
4.81
32.07
14
GBM, rec.
2.95
14.89
15
GBM, rec.
2.94
26.72
16
GBM, rec.
2.33
8.96
17
GBM, rec.
2.84
12.91
18
GBM, rec.
2.83
15.00
19
GBM
1.60
4.00
20
GBM
2.89
22.23
21
GBM, rec.
4.51
25.10
22
GBM, rec.
2.89
17.00
23
GBM
2.81
17.56
24
GBM
5.85
15.81
25
GBM, rec.
1.22
17.43
26
GBM, rec.
4.58
21.73
27
GBM, rec.
2.83
15.00
28
GBM
2.89
22.23
Anaplastic
29
1.95
10.26
astrocytoma
Anaplastic
1.73
7.86
30
astrocytoma
31
GBM
1.43
13.00
Ave.
2.94
16.83
Diagnosis

MET

1.98

T/N
ratio
1.78

2.83

1.35

1.80
3.03
3.13
3.89
3.03

1.04
2.37
1.82
2.54
1.89

1.96

2.68

4.82
2.19
4.08
3.41
3.01

4.38
3.22
6.07
2.54
2.64

5.82
3.49
3.63
5.39
5.54
4.27
3.10
6.47
6.14
3.40
6.07
4.57
1.46
5.90
4.27
7.82

4.44
3.45
3.67
2.51
2.55
3.30
1.24
3.87
3.23
2.91
6.07
3.41
1.76
2.71
3.30
4.68

5.94

4.01

2.18

1.79

4.27
4.72

2.12
3.21

SUVmaxTrue Point Biograph 16 (Siemens/CTI, Erlangen, Germany).
All subjects received an intravenous injection of MeAIB(513.6 ± 65.6 MBq) or MET (533.9 ± 35.0 MBq). Brain
PET/CT images were acquired 20 min after the radiotracer
injection in 1 bed position in both study. Emission images
were acquired for 5 min per bed position. The data werereconstructed using the ordered subsets expectationmaximization method using eight subsets, two iterations,and an array size of 256 × 256. For the attenuation correctionof PET/CT fusion images, the CT component was performed
according to a standard protocol with the following parameters: 140 kV; 50 mAs; tube rotation time, 0.5 s per rotation; slice thickness, 5 mm; and gap, 2 mm. An E-softworkstation (Siemens, Nashville, TN, USA) was used toconstruct PET/CT fusion images.

4Contrast Media & Molecular Imaging
p < 0.005

8

6
SUVmaxSUVmax

6

4

4

2

2

0

p < 0.005

8

BenignMalignant(a)0

BenignMalignant(b)

Figure 1: Comparison between benign and malignant groups by SUVmax of the lesions in MeAIB-PET (a) and MET-PET (b).

2.4. Image Analysis. PET images were interpreted and analyzed by two experienced nuclear medicine physicians withall the available clinical information, and then a final diagnosis was made in agreement. All PET images were fusedwith the MRI of each subject using the PMOD software,version 3.1 (PMOD; Zürich, Switzerland). We manuallyplaced an irregular region of interest (ROI) on the coregistered MRI image of each patient, and then these ROIs
were transferred to the PET image for the interpretation andcalculation of the uptake of each radiotracer. The maximum
standardized uptake value (SUVmax) was calculated forsemiquantitative analysis of MeAIB and MET uptake by thelesion. The tumor-to-contralateral normal brain tissue (T/N)
ratio was determined by dividing the tumor SUVmax by the
SUVmean of the contralateral hemisphere.
2.5. Statistics. All values are expressed as mean ± SD. All thestatistical analyses were performed using statistical software,
JMP version 12 (SAS Institute, Cary, NC, USA), in which
p values < 0.05 were considered to be statistically significant.
A comparison between each group was analyzed with the
Wilcoxon score for the unpaired data.

3. Results
3.1. Characteristics of Patients and Lesions. Final diagnosis
was confirmed pathologically by surgical resection, stereotactic biopsy, or by follow-ups of at least more than 6months. In the benign group of 12 patients, there were 11
astrocytoma grade II or less and one brain stem glioma. In
the malignant group of 19 patients, there were 7 with newly
diagnosed GBM, 10 with recurrent GBM, and 2 with anaplastic astrocytoma (Table 1).
3.2. Visual and Semiquantitative Analysis of MeAIB and MET
Uptake. Table 2 summarizes the SUVmax and T/N ratio of
MeAIB- and MET-PET in all patients. In MeAIB-PET imaging, the average SUVmax was 1.20 ± 1.29 for the benigngroup and 2.94 ± 1.22 for the malignant group (p < 0.005),

and the average T/N ratio was 3.77 ± 2.39 for the benigngroup and 16.83 ± 2.39 for the malignant group (p < 0.001).
In MET-PET, the average SUVmax was 3.01 ± 0.94 for the
benign group and 4.72 ± 1.61 for the malignant group(p < 0.005), and the average T/N ratio was 2.64 ± 1.40 for the
benign group and 3.21 ± 1.14 for the malignant group (n.s.).
The average SUVmax of tumors with MeAIB-PET was
significantly lower than that with MET-PET. However,
MeAIB uptake in the tumors by the malignant group and thebenign group showed significant statistical differences withp < 0.005 (Figure 1(a)). The average SUVmax of MET in thetumors of the malignant group was significantly higher thanthat of the benign group p < 0.005; however, there was a wide
overlap in MET uptake between the benign and malignant
groups, resulting in many false positive cases with MET-PET(Figure 1(b)).
For the analysis using the T/N ratio, there was a significant difference between the benign and malignant groups
with MeAIB-PET with p < 0.001, while no significant difference was observed with MET-PET (Figure 2).
Figures 3 and 4 show typical cases in the benign group,
which were diagnosed as astrocytoma grade II and lowgrade glioma after surgery or stereotactic biopsy. Highuptake of MET was in the tumor, while no significant uptakeof MeAIB was noted in both cases. In addition, other typicalcases in the malignant group are shown in Figures 5 and 8,
which were diagnosed as GBM and recurrent GBM; a clear
margined tumor was depicted as a high uptake of MeAIB
lesion. MET-PET also demonstrated the lesion with thephysiological uptake. Higher T/N ratio was noted in MeAIBPET image, respectively.
3.3. Diagnostic Accuracies of MeAIB- and MET-PET. As forthe differential diagnosis of brain tumors between the benign
and malignant groups, receiver operating characteristic
curve (ROC) analyses for the diagnostic accuracy of MeAIBPET and MET-PET using a semiquantitative analysis wereassessed (Figure 6). For ROC analysis using SUVmax, thearea under curve (AUC) value for MeAIB-PET was 0.83 with

Contrast Media & Molecular Imaging

5
8

p < 0.001

30

n.s.

20

T/N ratio

T/N ratio

6

10

4

2

0

Benign0

Malignant

Benign(a)

Malignant(b)

Figure 2: Comparison between benign and malignant groups by T/N ratio in MeAIB-PET (a) and MET-PET (b).

Glioma, grade II
MeAIB

MRI: FLAIR
MET
MeAIB

MeAIB/MRI

MET

MET/MRISUV
SUVmax T/N ratio
0.15
1.25
3.03

2.37

SUV
5.0

SUV
5.0

0

0

Figure 3: A case of a forty-year-old male who had a diffusely irregular-shaped mass in the left frontal lobe, which was diagnosed as
astrocytoma, grade II after surgery (benign group) (case #4). High uptake of MET was in the tumor, while no significant uptake of MeAIB
was noted.

standard error 0.090, 95% CI 0.65–1.00, and p < 0.005. The
AUC for MET-PET was 0.82 with standard error 0.076, 95%
CI 0.67–0.97, and p < 0.005. There was no significant difference in diagnosis accuracy between them (Figure 6(a)).
For ROC analysis using the T/N ratio, the AUC value for
MeAIB-PET was 0.97 with standard error 0.027, 95% CI
0.92–1.02, and p < 0.0001. The AUC for MET-PET was 0.69
with standard error 0.10, 95% CI 0.48–0.89, and p < 0.1.
These analyses indicated a better diagnosis accuracy for
MeAIB-PET for brain tumors than MET-PET (p < 0.01)(Figure 6(b)).
When the cutoff value was set as SUVmax  2.0 for
MeAIB-PET, the sensitivity, specificity, and accuracy were
73.7%, 91.7%, and 80.6%, respectively, while if the cutoff
value was set as SUVmax  3.5 for MET-PET, the sensitivity,

specificity, and accuracy were 73.7%, 75.0%, and 74.2%,
respectively. When the cutoff value was set as T/N ratio  7.0for MeAIB-PET, the sensitivity, specificity, and accuracy
were 94.7%, 91.7%, and 93.5%, respectively, while if thecutoff value was set as T/N ratio  3.0 for MET-PET, thesensitivity, specificity, and accuracy were 57.9%, 75.0%, and64.5%, respectively.
3.4. Relationship of SUVmax in the Lesion with MeAIB and
MET. Relationships between SUVmax of MeAIB and that of
MET of each lesion in both PET studies using logistic regression are shown in Figure 7. In the benign group, theSUVmax of MeAIB showed a nonsignificant linear relationship with that of MET (Figure 7(a)). On the contrary,6

Contrast Media & Molecular Imaging
Low-grade glioma
MeAIB
MeAIB/MRIMRI: FLAIR

MET
MeAIB
MET

MET/MRI

SUVmax T/N ratio
0.85
2.07
3.89
2.54

SUV
6.0

SUV
6.0

0

0

Figure 4: A case of a thirty-three-year-old male having newly diagnosed low-grade glioma in the right frontal lobe by stereotactic biopsy(benign group) (case #6). High uptake of MET was in the tumor, while no signiﬁcant uptake of MeAIB was noted.

GBM

FLAIR
MeAIB

MeAIB/MRIMRI Gd-DTPA
T1WI

MET
MeAIB
MET

MET/MRI

SUVmax T/N ratio
4.81
32.07
5.82
4.44

SUV
5.0

SUV
5.0

0

0

Figure 5: A case of a seventy-one-year-male who had newly diagnosed GBM in the left corpus callosum by stereotactic biopsy (malignant
group) (case #13). A clear margined tumor was depicted as a high uptake of MeAIB lesion. MET-PET also demonstrated the lesion with thephysiological uptake. Higher T/N ratio was noted in MeAIB-PET image.

in the malignant group, the SUVmax of MeAIB showed a weak
positive correlation with that of MET (p � 0.06, R2 � 0.20)(Figure 7(b)).

4. Discussion
System A amino acid transport is Na+- and energydependent, highly concentrative, and a putative regulatorof cell growth. Malignant transformation is associated withenhanced system A activity [22]. System A is speciﬁcallycapable of transporting N-methylated amino acids [23]. The
amino acid analog MeAIB was developed as an ideal tracer forin vivo transport measurements, as the compound is nonmetabolizable and concentrated in cells only via system A
transport [15, 20]. There are several reports regarding clinical
MeAIB-PET in patients with lymphoma [14], head and neckcancer [16], in addition to our previous study on pulmonary
and mediastinal mass lesions [18], and prostate cancer [19].
However, there have been no reports evaluating the usefulnessof MeAIB-PET for the diagnosis of brain tumors.

7

100

100

80

80

60

60

Sensitivity

Sensitivity

Contrast Media & Molecular Imaging

40

40

n.s.
20
0

p < 0.01

20

0

20

40
60
80
100% – specificity%

0

100

0

20

40
60
80
100% – specificity%

100

MeAIB
MET

MeAIB
MET
(a)

(b)

Y = –0.25X + 1.96
R2 = 0.035

n.s.

6

MeAIB SUVmax

MeAIB SUVmax

Figure 6: Receiver-operating characteristic curve (ROC) analyses for the diagnostic accuracy of MeAIB-PET and MET-PET using
semiquantitative analysis. (a) For ROC analysis using SUVmax, the area under the curve (AUC) value for MeAIB PET was 0.83 withstandard error 0.090, 95% CI 0.65–1.00, and p < 0.005. The AUC for MET-PET was 0.82 with standard error 0.076, 95% CI 0.67–0.97, andp < 0.005. There was no significance of diagnosis accuracy between them. (b) For ROC analysis using T/N ratio, the AUC value for MeAIB
PET was 0.97 with standard error 0.027, 95% CI 0.92–1.02, and p < 0.0001. The AUC for MET-PET was 0.69 with standard error 0.10, 95% CI
0.48–0.89, and p < 0.1. These analyses indicated better diagnosis accuracy of MeAIB-PET for brain tumors than MET-PET (p < 0.01).

4
2
0

0

4
2
MET SUVmax

6

(a)

6

Y = 0.33X + 1.38
R2 = 0.20

p = 0.06

4
2
0

0

2

4
6
MET SUVmax

8

10

(b)

Figure 7: Relationship between SUVmax of MeAIB and that of METof each lesion in both PETstudy using logistic regression. In the benigngroup, SUVmax of MeAIB showed nonsignificant linear relationship with that of MET (a). On the contrary, in the malignant group,
SUVmax of MeAIB showed a weak positive correlation with that of MET (p  0.06, R2  0.20) (b).

Our principal finding is that the diagnostic accuracy of
MeAIB using T/N ratio was better than those of MET-PET
when differentiating benign and malignant brain lesions.
The T/N ratio with MeAIB-PET was higher than that with
MET because of the faint uptake of MeAIB by normal brains(Figures 3–5 and 8). The reason for this is that MeAIB has
difficulty permeating the blood-brain barrier (BBB) [24].
Using the T/N ratio, MeAIB-PET displayed higher diagnostic accuracy in distinguishing between the benign andmalignant groups (Figure 6), which resulted in showing
relatively low false negative findings than MET-PET.
Therefore, MeAIB-PET may be useful for the diagnosis ofmalignant brain tumors with broken BBB and high expressions of system A transport. This high T/N ratio may
result in the clear contrast between surrounding brain tissues
and the marginal edge of malignant brain tumor. Moreover,

MeAIB-PET may contribute to more accurate depictions of
the tumor margin when stereotactic surgery/biopsy or stereotactic radiotherapy is considered for the treatment ofmalignant brain tumors. The uptake of MeAIB in brain
tumors was lower than that of MET. This may represent
a difference in expression between system A and L aminoacid transport in tumors. Considering the results of therelationships between SUVmax of MeAIB and that of MET
for each tumor in the malignant group, SUVmax of MeAIB
showed a weak linear relationship, and not significant, withthat of MET.
MET is mainly transported by system L amino acidtransporters. MET-PET has been widely used for brain
tumor imaging [25–28]. However, for tumor grading using
MET-PET, Hatakeyama et al. reported that the differences of
MET SUVmax and T/N ratios between grades II and III

8Contrast Media & Molecular Imaging
GBM, recurrence
MeAIB
MeAIB/MRIMRI: FLAIR
MET
MeAIB
MET

MET/MRI

SUVmax T/N ratio
2.83
15.0
4.27
3.30

SUV
5.0

SUV
5.0

0

0

Figure 8: A case of a sixty-eight-year-old female who had received chemoradiotherapy before for GBM in the left temporal lobe (malignant
group) (case #18). A clear margined tumor was depicted as a high uptake of MeAIB lesion. MET-PETalso demonstrated the lesion; however,
the margin of the lesion was unclear due to the physiological uptake of MET in the brain. Recurrent GBM was conﬁrmed after stereotactic
biopsy.

gliomas were not statistically signiﬁcant and that low-grade
gliomas with oligodendroglial components had relatively
high MET uptake [25]. Sasaki et al. noted that MET was
highly useful both for detecting astrocytoma and for differentiating between benign and malignant astrocytomas.
However, it was not suﬃciently useful to evaluate the histological grade of the astrocytomas [27]. In the present
study, although MET-PET showed the possibility of distinguishing between low-grade and high-grade astrocytoma
using SUVmax, the T/N ratio was not useful for tumor
grading (Figure 2), as suggested in previous reports. Physiological uptake of MET by the brain via system L amino acidtransporters is considered to be one of the reasons for thisresult because MET is known to be utilized for the physiological metabolism of normal brain tissues as a substrate forprotein synthesis, neurotransmitters, and energy production[2, 10, 11, 29]. In this study, indeed, MET-PET had a tendency to show false positive ﬁndings more than MeAIBPET. The physiological uptake of MET by the normal brain
tissue is considered as one of the reasons. In consideringother amino acid PET imaging, Inoue et al. investigated anamino acid PET imaging using L-3-[F-18]-ﬂuoro-alphamethyl tyrosine (FAMT) and reported the mean value of
SUV of the brain tumor as 2.83 ± 1.57 in FAMT-PET [30].
This is similar to the result of MET-PET because FAMT istransported into cancer cells via system L amino acidtransporter [31].
In terms of the study limitations, there were a relatively
small number in the study population that participated inthis study. Most of them are astrocytoma grade II or less andGBM. And there were ten recurrent GBM in addition to
newly diagnosed GBM included in this study. Recurrent
tumors analyzed in this study were lesions 6 months or more

after successful treatment, so there might be little eﬀect of
the treatment for analysis of this PET imaging study.
However, detailed examination with large number of subjects was considered to be needed in terms of inﬂuences after
surgery or chemotherapy on PET image. Moreover, further
study is also needed, including that of brain tumors otherthan astrocytic tumors such as metastatic brain tumors or
CNS lymphoma.

5. Conclusions
We investigated system A amino acid transport PET imaging, MeAIB-PET, in patients with astrocytoma and GBM
and compared the diagnostic results to those obtained by
MET-PET. MeAIB-PETcould provide better assessments for
detecting malignant-type brain tumors. In a diﬀerential
diagnosis between low-grade and high-grade astrocytoma,
MeAIB-PET is a useful diagnostic imaging tool, especially inevaluations using the T/N ratio.

Additional Points
Highlights. The uptake of MeAIB in brain tumors was lower
but showed higher image contrast than those of MET. Using
the T/N ratio, MeAIB-PET showed higher diagnostic accuracy
compared to MET-PET. MeAIB-PET contributes to moreaccurate depictions of the tumor margin. MeAIB-PETprovides
better assessments for detecting malignant brain tumors.

Conflicts of Interest
The authors declare that there are no conﬂicts of interest
regarding the publication of this study.

Contrast Media & Molecular Imaging

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